The neural control of micturition.

Abstract

Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

a | Primary afferent pathways to the L6 spinal cord of the rat project to regions of the dorsal commissure (DCM), the superficial dorsal horn (DH) and the sacral parasympathetic nucleus (SPN) that contain parasympathetic preganglionic neurons. The afferent nerves consist of myelinated (Aδ) axons, which respond to bladder distension and contraction, and unmyelinated (C) axons, which respond to noxious stimuli. b | Spinal interneurons that express c-fos following the activation of bladder afferents by a noxious stimulus (acetic acid) to the bladder are located in similar regions of the L6 spinal segment. c | Spinal interneurons involved in bladder reflexes (labelled by transneuronal transport of pseudorabies virus injected into the urinary bladder) are localized to the regions of the spinal cord that contain primary afferents and c-fos. Some of these interneurons provide excitatory and inhibitory inputs to the parasympathetic preganglionic neurons located in the SPN. d | The laminar organization of the cat sacral spinal cord, showing the location of parasympathetic preganglionic neurons in the intermediolateral region of laminae V and VII (shaded area). CC, central canal; IL, intermediolateral nucleus; LT, Lissauer's tract; VM, ventromedial nucleus (Onuf's nucleus).

a | Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia. A region in the rostral pons (the pontine storage centre) might increase striated urethral sphincter activity. b | Voiding reflexes. During the elimination of urine, intense bladder-afferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition centre. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal outflow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the periaqueductal grey (PAG) before reaching the pontine micturition centre. Note that these diagrams do not address the generation of conscious bladder sensations, nor the mechanisms that underlie the switch from storage to voiding, both of which presumably involve cerebral circuits above the PAG. R represents receptors on afferent nerve terminals.

Reflex voiding responses in an infant, a healthy adult and a paraplegic patient

Combined cystometrograms and sphincter electromyograms (EMGs, recorded with surface electrodes), allowing a schematic comparison of reflex voiding responses in an infant (a) and in a paraplegic patient (c) with a voluntary voiding response in a healthy adult (b). The abscissa in all recordings represents bladder volume in millilitres; the ordinates represent electrical activity of the EMG recording and detrusor pressure (the component of bladder pressure that is generated by the bladder itself) in cm H2O. On the left side of each trace (at 0 ml), a slow infusion of fluid into the bladder is started (bladder filling). In part b the start of sphincter relaxation, which precedes the bladder contraction by a few seconds, is indicated (‘start’). Note that a voluntary cessation of voiding (‘stop’) is associated with an initial increase in sphincter EMG and detrusor pressure (a myogenic response). A resumption of voiding is associated with sphincter relaxation and a decrease in detrusor pressure that continues as the bladder empties and relaxes. In the infant (a) sphincter relaxation is present but less complete. On the other hand, in the paraplegic patient (c) the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, involuntary bladder contractions (detrusor overactivity) occur in association with sphincter activity. Each wave of bladder contraction is accompanied by simultaneous contraction of the sphincter (detrusor–sphincter dyssynergia), hindering urine flow. Loss of the reciprocal relationship between the bladder and the sphincter in paraplegic patients thus interferes with bladder emptying.

Organization of the parasympathetic excitatory reflex pathway to the detrusor muscle

This scheme is based on results from electrophysiological studies in cats. Micturition is initiated by a supraspinal reflex pathway that passes through a centre in the brainstem. The pathway is triggered by myelinated afferents (Aδ-fibres), which are connected to the tension receptors in the bladder wall. Injury to the spinal cord above the sacral segments interrupts the connections between the brain and spinal autonomic centres and initially blocks micturition. However, following cord injury a spinal reflex mechanism (shown in green) emerges that is triggered by unmyelinated vesical afferents (C-fibres); the A-fibre afferent inputs are ineffective. The C-fibre reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fibre bladder afferents by installation of ice water into the bladder (cold stimulation) activates voiding responses in patients with spinal cord injury. Capsaicin (20–30 mg subcutaneously) blocks the C-fibre reflex in cats with spinal lesions but does not block micturition reflexes in intact cats. Intravesical capsaicin also suppresses detrusor hyperreflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction.